ES2956794T3 - Controlled release of 25-hydroxyvitamin D - Google Patents

Abstract

The invention provides a pharmaceutical composition comprising an oral formulation of 25-hydroxyvitamin D for use in a method of treating secondary hyperparathyroidism in a human patient having chronic kidney disease. The treatment method comprises administering the composition to the patient and the patient is treated without causing supraphysiological spikes in blood levels of 25-hydroxyvitamin D. (Automatic translation with Google Translate, no legal value)

Description

DESCRIPTION

Controlled release of 25-hydroxyvitamin D

Background

Dissemination field

The disclosure relates generally to controlled release pharmaceutical compositions. More particularly, the invention relates to a controlled release formulation for oral administration of a vitamin D compound.

Brief description of related technology

Cholecalciferol and ergocalciferol (collectively referred to as “vitamin D”) are fat-soluble secasteroid precursors to vitamin D prohormones. Vitamin D metabolites known as 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 (collectively referred to herein as “25 -hydroxyvitamin D”) are fat-soluble steroid prohormones for vitamin D hormones that contribute to the maintenance of normal levels of calcium and phosphorus in the bloodstream.

Cholecalciferol and ergocalciferol are normally present at low, stable concentrations in human blood. Slight, if any, increases in blood vitamin D levels occur after meals because unsupplemented diets are low in vitamin D, even those containing foods fortified with vitamin D. Nearly all of the vitamin supply Human D comes from fortified foods, exposure to sunlight or dietary supplements, becoming the latter increasingly important source. Blood levels of vitamin D rise only gradually, if at all, after exposure to sunlight as cutaneous 7-dehydrocholesterol is modified by UV radiation to pre-vitamin D3, which undergoes thermal conversion in the skin to cholecalciferol for a period of several days before circulating in the blood. In contrast, supplements such as those currently available produce marked increases in intraluminal, blood and intracellular levels of vitamin D proportional to the dose administered.

Both cholecalciferol and ergocalciferol are metabolized to prohormones by enzymes mainly located in the liver of the human body. Cholecalciferol is metabolized to the prohormone 25-hydroxyvitamin D3, and ergocalciferol is metabolized to two prohormones, 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2. Cholecalciferol and ergocalciferol can also be metabolized to prohormones outside the liver in certain cells, such as enterocytes, by enzymes that are identical or similar to those found in the liver. Raising concentrations of any precursor increases prohormone production; Similarly, decreasing concentrations of precursors decreases hormone production. Sudden increases in blood levels of cholecalciferol and/or ergocalciferol (“cholecalciferol/ergocalciferol”) may transiently increase intracellular concentrations of vitamin D, accelerate production of prohormones, and elevate intracellular and blood concentrations of prohormones. Sudden increases in blood levels of cholecalciferol and/or ergocalciferol can also saturate the enzymes that produce prohormones, resulting in excess vitamin D being catabolized or diverted to long-term storage in adipose tissue. Vitamin D stored in adipose tissue is less available for future conversion to prohormones. Sudden increases in intraluminal vitamin D levels following ingestion of current oral supplements may directly elevate vitamin D and prohormone concentrations in local enterocytes, thereby exerting “first-pass” effects on calcium metabolism and Phosphorus in the small intestine.

Vitamin D prohormones are further metabolized in the kidneys to potent hormones. The prohormone 25-hydroxyvitamin D3 is metabolized to a hormone 1a,25-dihydroxyvitamin D3 (or calcitriol); Likewise, 25-hydroxyvitamin D2 and 24(S)-hydroxyvitamin D2 are metabolized to hormones known as 1a,25-dihydroxyvitamin D2 and 1a,24(S)-dihydroxyvitamin D2, respectively. The production of these hormones from prohormones can also occur outside the kidney in cells that contain the required enzyme(s).

Rises in blood or intracellular concentrations of prohormones may promote excessive extrarenal production of hormones, resulting in local adverse effects on calcium and phosphorus metabolism. Such elevations may also inhibit hepatic production of prohormones from subsequent supplemental vitamin D and promote catabolism of both vitamin D and 25-hydroxyvitamin D in the kidney and other tissues.

Blood vitamin D hormone concentrations remain generally constant throughout the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained changes in intake of vitamin D. Normally, blood levels of cholecalciferol, ergocalciferol, and the three vitamin D prohormones are also constant throughout the day, given a sustained, adequate supply of vitamin D from exposure to sunlight and a unsupplemented diet. However, blood levels of cholecalciferol and ergocalciferol may increase markedly. after administration of currently available vitamin D supplements, especially in doses that far exceed the amounts necessary to prevent vitamin D deficiency, rickets or osteomalacia.

Vitamin D hormones have essential roles in human health that are mediated by intracellular vitamin D receptors (VDR). In particular, vitamin D hormones regulate blood calcium levels by controlling the adsorption of dietary calcium by the small intestine and the reabsorption of calcium by the kidneys. Excessive levels of hormones can cause abnormally high levels of calcium in the urine (hypercalciuria), calcium in the blood (hypercalcemia), and phosphorus in the blood (hyperphosphatemia). Vitamin D hormones are also involved in the regulation of cell differentiation and growth, secretion of parathyroid hormone (PTH) by the parathyroid glands, and normal bone formation and metabolism. Additionally, vitamin D hormones are required for the normal functioning of the muculoskeletal, immune, and renin-angiotensin systems. Numerous other roles for vitamin D hormones have been postulated and explained based on the documented presence of intracellular VDRs in almost every human tissue.

Secondary hyperparathyroidism is a disorder that develops primarily due to vitamin D deficiency. It is characterized by abnormally elevated blood levels of PTH and, in the absence of early detection and treatment, is associated with hyperplasia of the parathyroid gland and a constellation of metabolic bone diseases. It is a common complication of chronic kidney disease (CKD) with increasing incidence as CKD progresses. Secondary hyperparathyroidism can also develop in individuals with healthy kidneys, due to environmental, cultural or nutritional factors that prevent adequate supply of vitamin D.

Regarding secondary hyperparathyroidism and its appearance in CKD, there is a progressive loss of cells in the proximal nephrons, the main site for the synthesis of vitamin D hormones (collectively “1,25-dihydroxyvitamin D”) from 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. Furthermore, the loss of functional nephrons produces a retention of excess phosphorus that reduces the activity of renal 25-hydroxyvitamin D-1ahydroxylase, the enzyme that catalyzes the reaction that produces vitamin D hormones. These two facts are responsible for the low levels. serum 1,25-dihydroxyvitamin D commonly found in patients with moderate to severe CKD when vitamin D supply is adequate.

Reduced serum 1,25-dihydroxyvitamin D levels result in increased, and ultimately excessive, secretion of PTH by direct and indirect mechanisms. The resulting hyperparathyroidism produces markedly increased bone turnover and its sequelae of renal osteodystrophy, which may include a variety of other diseases, such as osteitis fibrosa cystica, osteomalacia, osteoporosis, extraskeletal calcification and related disorders, e.g., bone pain, inflammation. periarticular and Mockerberg sclerosis. Reduced serum levels of 1,25-dihydroxyvitamin D can also produce muscle weakness and growth retardation with skeletal deformities (most commonly seen in pediatric patients).

Blood levels of 1,25-dihydroxyvitamin D are precisely regulated by a feedback mechanism involving PTH. Renal 1a-hydrolase (or CYP27B1) is stimulated by PTH and inhibited by 1,25-dihydroxyvitamin D. When blood levels of 1,25-dihydroxyvitamin D fall, the parathyroid glands sense this change through vitamin D receptors. D intracellular and secrete PTH. Secreted PTH stimulates the expression of renal CYP27B1 and thereby increases the production of vitamin D hormones. As blood concentrations of 1,25-dihydroxyvitamin D increase again, the parathyroid glands further attenuate PTH secretion. As blood levels of PTH fall, kidney production of vitamin D hormones decreases. Increasing blood levels of 1,25-dihydroxyvitamin D also directly inhibits further production of vitamin D hormones by CYP27B1.

PTH secretion may be abnormally suppressed in situations where blood concentrations of 1,25-dihydroxyvitamin D become excessively elevated, as may occur in certain disorders such as sarcoidosis or as a result of bolus doses of vitamin hormone replacement therapies. D. Oversuppression of PTH secretion can produce or exacerbate alterations in calcium homeostasis. The parathyroid glands and renal CYP27B1 are intensely sensitive to changes in blood concentrations of vitamin D hormones so that serum 1,25-dihydroxyvitamin D is tightly controlled, fluctuating up or down by less than 20% during any given time. 24 hour period. In contrast to renal production of vitamin D hormones, extrarenal production is not under precise feedback control.

Blood levels of, and regulation of, 1,25-dihydroxyvitamin D and the substrate prohormone 25-hydroxyvitamin D may also be affected by vitamin D hormone analogues, such as 1ahydroxyvitavin D2 and 19-nor-1. ,25-dihydroxyvitamin D2.

The actions of vitamin D hormones on specific tissues depend on the degree to which they bind to (or occupy) intracellular VDRs in those tissues. Cholecalciferol and ergocalciferol have VDR affinities that are estimated to be at least 100 times lower than those of the vitamin D hormones. As a consequence, physiological concentrations of cholecalciferol and ergocalciferol exert few, if any, biological actions without prior metabolism. to vitamin D hormones. However, supraphysiological levels of cholecalciferol and ergocalciferol, in the range of 10 to 1,000 times higher than normal, can sufficiently occupy the VDR and exert actions such as vitamin D hormones. Similarly, the prohormones 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 have essentially identical affinities for the VDRs that have also been estimated to be at least 100 times lower than those of the vitamin D hormones. As a consequence, physiological concentrations of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 have few, if any, biological actions without prior metabolism to vitamin D hormones. However, supraphysiological levels of 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3, in the range of 10 to 1,000 times greater than normal, can sufficiently occupy the VDR to exert actions such as vitamin D hormones.

The production of vitamin D prohormones decreases when there is a low supply of vitamin D, as in conditions such as vitamin D insufficiency or vitamin D deficiency (alternatively, hypovitaminosis D). Low production of vitamin D prohormones results in low blood levels of 25-hydroxyvitamin D. Inadequate vitamin D supply often develops in individuals who are infrequently exposed to sunlight, have chronically inadequate vitamin D intakes, or suffer from conditions that reduce intestinal absorption of fat-soluble vitamins (such as vitamin D). It has recently been reported that the majority of individuals living in Nordic latitudes have inadequate supplies of vitamin D. If left untreated, inadequate supplies of vitamin D can lead to serious bone disorders, including rickets and osteomalacia.

The Institute of Medicine (IOM) of the National Academy of Sciences has concluded that an adequate intake (AI) of vitamin D for a healthy individual ranges from 200 to 600 IU per day, depending on the age and sex of the individual. See Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Dietary references intakes: calcium, phosphorus, magnesium, vitamin D, and fluorine, Washington, DC: National Academy Press (1997), incorporated herein by reference. The AI for vitamin D was defined primarily based on the serum level of 25-hydroxyvitamin D sufficient to prevent vitamin D deficiency, rickets, or osteomalacia (or at least 11 ng/ml). The IOM also established a tolerable upper intake level (UL) for vitamin D of 2,000 IU per day, based on evidence that higher doses are associated with an increased risk of hypercalciuria, hypercalcemia, and related sequelae, including cardiac arrhythmias, seizures. and widespread vascular and other soft tissue calcification.

Currently available oral vitamin D supplements are far from ideal for achieving and maintaining optimal blood levels of 25-hydroxyvitamin D. These preparations typically contain 400 IU to 5,000 IU of vitamin D3 or 50,000 IU of vitamin D2 and are formulated to a rapid or immediate release in the digestive system. When administered at chronically high doses, as is often required for vitamin D replacement, these products have significant and often serious limitations that are summarized below.

High doses of immediate-release vitamin D supplements produce sharp increases in blood vitamin D levels, thereby promoting: (a) storage of vitamin D in adipose tissue, which is undesirable because stored vitamin D it is less available for subsequent hepatic conversion to 25-hydroxyvitamin D; (b) hepatic catabolism of vitamin D to metabolites, which are less useful or no longer useful in increasing blood 25-hydroxyvitamin D levels, through 24- and/or 26-hydroxylation; (c) excessive intracellular 24- or 25-hydroxylation of vitamin D, resulting in an increased risk of hypercalciuria, hypercalcemia, and hyperphosphatemia.

High doses of immediate-release vitamin D supplements also produce sudden increases or spikes in intracellular and blood 25-hydroxyvitamin D levels, thereby promoting: (a) excessive extrarenal production of vitamin D hormones and resulting in local abnormalities in calcium and phosphorus homeostasis and increased risk of hypercalciuria, hypercalcemia and hyperphosphatemia; (b) accelerated catabolism of both vitamin D and 25-hydroxyvitamin D through 24- and/or 26-hydroxylation in the kidney and other tissues; (c) decreased hepatic production of vitamin D prohormones, making effective replacement of vitamin D insufficiency or deficiency unnecessarily difficult; and (d) local abnormalities in calcium and phosphorus homeostasis mediated by direct binding to VDR.

Furthermore, high doses of immediate-release vitamin D supplements produce supraphysiological pharmacological concentrations of vitamin D, for example, in the lumen of the duodenum, promoting: (a) 25-hydroxylation in enterocytes and local stimulation of the intestinal absorption of calcium and phosphorus, which produces an increased risk of hypercalciuria, hypercalcemia and hyperphosphatemia; (b) vitamin D catabolism via 24- and/or 26-hydroxylation in local enterocytes, resulting in decreased systemic bioavailability; and (c) absorption primarily through chylomicrons, resulting in increased hepatic catabolism.

Vitamin D supplementation above the UL is often needed in certain individuals; However, currently available oral vitamin D supplements are not very suitable for maintaining blood levels of 25-hydroxyvitamin D given the problems of administering high doses of immediate-release vitamin D compounds.

Blood concentrations of vitamin D hormones also generally remain constant throughout the day in healthy individuals, but can vary significantly over longer periods of time in response to seasonal changes in sunlight exposure or sustained alterations in intake of vitamin D. Marked differences in normal vitamin D hormone levels are commonly observed among healthy individuals, with some individuals having stable concentrations as low as approximately 20 pg/ml and others as high as approximately 70 pg/ml. Because of this wide normal range, medical professionals have difficulty interpreting isolated laboratory determinations of total serum 1,25-hydroxyvitamin D; A value of 25 pg/ml may represent a normal value for one individual or a relative deficiency in another.

Transiently low blood levels of 1,25-dihydroxyvitamin D stimulate the parathyroid glands to secrete PTH for short periods that end when normal blood levels of vitamin D hormones are restored. In contrast, chronically low blood levels of 1,25-dihydroxyvitamin D continually stimulate the parathyroid glands to secrete PTH, resulting in a disorder known as secondary hyperparathyroidism. Chronically low hormone levels also decrease intestinal calcium absorption, resulting in reduced blood calcium concentrations (hypocalcemia) that additionally stimulate PTH secretion. Continually stimulated parathyroid glands become increasingly hyperplastic and eventually develop resistance to regulation by vitamin D hormones. Without early detection and treatment, secondary hyperparathyroidism progressively increases in severity, resulting in debilitating metabolic bone diseases, including osteoporosis and renal osteodystrophy.

Chronically low blood levels of 1,25-dihydroxyvitamin D develop when there is insufficient renal CYP27B1 to produce the required supply of vitamin D hormones, a situation that commonly arises in CKD. Renal CYP27B1 activity decreases as glomerular filtration rate (GFR) falls below approximately 60 ml/min/1.73 m2 due to the loss of functional nephrons. In end-stage renal disease (eRt), when the kidney fails completely and hemodialysis is required for survival, renal CYP27B1 often becomes completely absent. Any remaining CYP27B1 is greatly inhibited by elevated serum phosphorus (hyperphosphatemia) caused by inadequate renal excretion of nutritional phosphorus.

Chronically low blood levels of 1,25-dihydroxyvitamin D also develop due to a deficiency of vitamin D prohormones, as renal hormone production cannot continue without the required precursors. Prohormone production is markedly decreased when cholecalciferol and ergocalciferol are in low supply, a condition frequently described by terms such as “vitamin D insufficiency,” “vitamin D deficiency,” or “hypovitaminosis D.” Therefore, measuring blood levels of 25-hydroxyvitamin D has become the accepted method among healthcare professionals to monitor vitamin D status. Recent studies have documented that the vast majority of CKD patients have low levels. low blood levels of 25-hydroxyvitamin D, and that the prevalence of vitamin D insufficiency and deficiency increases as CKD progresses.

It turns out that the individuals most vulnerable to developing low blood levels of 1,25-dihydroxyvitamin D are those with CKD. Most CKD patients typically have decreased levels of renal CYP27B1 and a shortage of 25-hydroxyvitamin D prohormones. Not surprisingly, most CKD patients develop secondary hyperparathyroidism. Unfortunately, early detection and treatment of secondary hyperparathyroidism in CKD patients is rare, let alone prevention.

The National Kidney Foundation (NKF) has recently focused the attention of the medical community on the need for early detection and treatment of secondary hyperparathyroidism by publishing Kidney Disease Outcomes Quality Initiative (K/ ^d O ^q I) Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease [Am. J. Kidney Dis. 42:S1-S202, 2003)]. The K/DOQI guidelines identified the primary etiology of secondary hyperparathyroidism as chronically low blood levels of 1,25-dihydroxyvitamin D and recommended regular screening in CKD stages 3 to 5 for elevated blood PTH levels relative to target ranges. Stage-specific PTH, which for stage 3 is 35-70 pg/ml (equivalent to 3.85-7.7 pmol/l), for stage 4 is 70-110 pg/ml (equivalent to 7.7- 12.1 μmol/l) and for stage 5 it is 150-300 pg/ml (equivalent to 16.5-33.0 μmol/l) (defined in the K/DOQI guideline No. 1). In the event that screening reveals that an iPTH value is above the target ranges for CTE stages 3 and 4, the guidelines recommended a complementary evaluation of total serum 25-hydroxyvitamin D to detect possible insufficiency or deficiency of vitamin D. If 25-hydroxyvitamin D was observed below 30 ng/ml, the recommended intervention was vitamin D replacement therapy using orally administered ergocalciferol. If 25-hydroxyvitamin D was observed above 30 ng/ml, the recommended intervention was vitamin D hormone replacement therapy using known oral or intravenous hormones or vitamin D analogues. The guidelines did not recommend the concurrent application of vitamin D replacement and vitamin D hormone replacement therapies, consistent with the Food and Drug Administration-mandated notices on package inserts for vitamin D hormone replacement products.

The NKF K/DOQI guidelines defined vitamin D sufficiency as serum 25-hydroxyvitamin D levels > 30 ng/ml. The recommended vitamin D replacement therapy for patients with “vitamin D insufficiency,” defined as serum 25-hydroxyvitamin D of 16-30 ng/ml, was 50,000 IU per month of oral vitamin D2 for 6 months, given well in single monthly doses or in divided doses of approximately 1,600 IU per day. The recommended replacement therapy for patients with “vitamin D deficiency” was more aggressive: for “moderate” deficiency, defined as serum 25-hydroxyvitamin D of 5-15 ng/ml, the guidelines recommended 50,000 IU per week of vitamin Oral D2 for 4 weeks, followed by 50,000 IU per month for another 5 months; for “severe” deficiency, Defined as serum 25-hydroxyvitamin D below 5 ng/ml, the guidelines recommended 50,000 IU/week of oral vitamin D2 for 12 weeks, followed by 50,000 IU/month for another 3 months. Doses of 50,000 IU per week are approximately equivalent to 7,000 IU per day.

Compendium

One aspect of the disclosure relates to a waxy, solid or semi-solid pharmaceutical formulation for the controlled release of a vitamin D compound in the digestive tract of a subject who ingests the formulation. The formulation includes a controlled release waxy carrier, a lipoid agent, an oleaginous vehicle for the vitamin D compound and a vitamin D compound. The formulation provides controlled release of the vitamin D compound incorporated therein. The formulation preferably is free or essentially free of disintegrants.

In another aspect, a controlled release pharmaceutical form of a vitamin D compound is disclosed that contains (a) a pharmacologically active amount of a vitamin D compound and (b) a release modifying agent that controls the rate of release of the compound. of vitamin D from the dosage form to reduce Cmax and/or delay Tmax and/or decrease Cmax24h/C24h as described herein. Preferably both Cmax is reduced and Tmax is delayed (increased). Such controlled release dosage forms show the advantage of increased elimination half-life and/or reduced toxicity and/or improved potency (e.g., ability to administer a reduced dose of the vitamin D compound, or administer less frequently, to achieve a better effect). similar therapeutic compared to an immediate release dosage form). In some embodiments, the release modifying agent includes a controlled release waxy carrier, a lipoid agent, and an oleaginous carrier for the vitamin D compound. Optionally, the release modifying agent and dosage forms of the invention They may be free or substantially free of disintegrants.

Therefore, a method of administering an amount of a vitamin D compound to a patient is disclosed so that the maximum serum concentration of the vitamin D compound in a dose range (Cmax) is reduced compared to the Cmax for an amount equivalent of a vitamin D compound administered by bolus IV injection and/or an equivalent immediate-release oral dosage form. Similarly, the invention provides a controlled release dosage form having an amount of a vitamin D compound that, when administered to a patient, produces a Cmax less than the Cmax for an equivalent amount of a vitamin D compound administered. by bolus IV injection and/or by an equivalent immediate-release oral dosage form. For example, the reduction is preferably by a factor of at least 20%, 30%, 40%, 50%, 60%, 70% or 80%.

Also disclosed is a method of administering an amount of a vitamin D compound to a patient such that the maximum change in serum concentration of a vitamin D compound over a dose range is reduced compared to an equivalent amount of a compound. of vitamin D administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. Similarly, the invention provides a controlled release dosage form having an amount of a vitamin D compound that, when administered to a patient, produces a maximum change in the serum concentration of a vitamin D compound over a range dose less than an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. For example, the reduction is preferably by a factor of at least 20%, 30%, 40%, 50%, 60%, 70% or 80%.

Also disclosed is a method of administering an amount of a vitamin D compound to a patient such that the ratio of the maximum serum concentration in the 24 hours after administration of a vitamin C compound to the concentration 24 hours later of administration (Cmax24h/C24h) is reduced compared to an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. Similarly, the invention provides a controlled release dosage form having an amount of a vitamin D compound that, when administered to a patient, produces a Cmax24h/C24h less than an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. For example, the reduction is preferably by a factor of at least 20%, 30%, 40%, 50%, 60%, 70% or 80%.

Also disclosed is a method of administering an amount of a vitamin D compound to a patient such that the elimination half-life (ti/2) of a vitamin D compound increases compared to the ti/2 for an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. Similarly, the invention provides a controlled release dosage form having an amount of a vitamin D compound that, when administered to a patient, produces a ti/2 of a vitamin D compound greater than that of ti/2 of an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. For example, the increase is preferably by a factor of at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or 300%.

Also disclosed is a method of administering an amount of a vitamin D compound to a patient such that the time for the plasma concentration of a vitamin D compound to reach its maximum in a dose range after administration (Tmax) increases compared to the Tmax for an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. Similarly, the invention provides a controlled release dosage form having an amount of a vitamin D compound that, when administered to a patient, produces a Tmax greater than that of an equivalent amount of a vitamin D compound administered by bolus IV injection and/or by an equivalent immediate-release oral dosage form. For example, the increase is preferably by a factor of at least 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 500% or 1000%.

In various embodiments, the compositions are contemplated to be associated with one or more benefits, such as significantly: increasing the bioavailability of the contained vitamin D compound by promoting absorption directly into the bloodstream rather than into the lymphatic system via chylomicrons. ; increase the bioavailability of vitamin D compound content by reducing catabolism in the enterocytes of the upper small intestine; reduce the undesirable effects of the first pass of the vitamin D compound contained in the duodenum; prevent the production of adverse supraphysiological surges in blood levels of the vitamin D compound; prevent the reduction of blood concentrations of the vitamin D compound below optimal levels; restore blood concentrations of the vitamin D compound to optimal levels; maintaining blood concentrations of the vitamin D compound at such optimal levels; reduce alterations in vitamin D metabolism and related abnormalities in calcium, phosphorus and PTH homeostasis; and decrease the risk of serious side effects associated with vitamin D replacement and replacement, including hypercalciuria, hypercalcemia, hyperphosphatemia, and vitamin D toxicity. One or more of the above benefits may be seen independently or in combination.

For the compositions and methods described herein, preferred steps, preferred components, preferred compositional ranges thereof, and preferred combinations of the above may be selected from various examples provided herein.

The claimed invention provides a pharmaceutical composition for use in a treatment method defined in claim 1. Specifically, the claimed invention provides a pharmaceutical composition comprising an oral formulation of 25-hydroxyvitamin D3 for use in a treatment method of secondary hyperparathyroidism in a human patient suffering from chronic kidney disease, wherein the treatment method comprises administering the composition to the patient, wherein the patient is treated without causing supraphysiological increases in blood 25-hydroxyvitamin D3, and wherein the pharmaceutical composition comprises 25-hydroxyvitamin D3 together with a release modifying agent that controls the release rate of the vitamin D compound from the dosage form to reduce Cmax and/or delay Tmax and/or decrease Cmax24h/C24h.

Brief description of the figures

To further facilitate the understanding of the present invention, twenty-seven figures are attached thereto.

Figure 1 to Figure 8 show graphs of the change in serum 25-hydroxyvitamin D3 levels during the first 24 hours after administration for groups of test subjects administered oral pharmaceutical formulations that include 25-hydroxyvitamin D3 according to example 1. Furthermore, Figure 7 shows an overlay of comparative data for immediate and controlled release formulations.

Figure 9 to Figure 11 show graphs of the change in serum 25-hydroxyvitamin D3 levels during the study period of example 1 for the controlled release formulation of group 7 according to the invention, the immediate release formulation of group 9 according to the prior art, and intravenous administration of group 10.

Figure 12 shows an overlay plot of the data in Figure 9 and Figure 10 for groups 7 and 9, respectively, in Example 1.

Figure 13 to Figure 18 show the mean pharmacokinetic profile for miniature pigs administered modified and immediate release oral formulations of 25-hydroxyvitamin D3 according to Example 2. Figure 19 shows a comparison of the pharmacokinetic profiles for the LM and LI formulations of 250 μg of 25-hydroxyvitamin D3 according to example 2.

Figure 20 shows the profiles of the mean uncorrected serum 25-hydroxyvitamin D3 concentration versus time for groups 1 to 3 of miniature pigs after administration of 25-hydroxyvitamin D3 according to example 3.

Figure 21 to Figure 23 show the profiles of the mean basal serum 25-hydroxyvitamin D3 concentration corrected against time for groups 1 to 3 according to example 3.

Figure 24 shows the mean change in parathyroid hormone levels for group 1 animals from predose to day 21, and figure 25 shows the mean change in parathyroid hormone levels for group 2 animals from predose to day 21. day 21, from example 3.

Figure 26 shows the profiles of the mean concentration of 25-hydroxyvitamin D3 in serum versus time for groups 1 to 5 of Beagle dogs administered modified release capsules of 25-hydroxyvitamin D3 according to example 4.

Figure 27 shows a dissolution release profile for 250 μg capsules according to Example 2, which showed an average release of approximately 72% of 25-hydroxyvitamin D3 at 24 hours.

Detailed description

As used herein, the term “vitamin D toxicity” is intended to refer to the side effects suffered from excessively elevated blood levels of vitamin D, including one or more of nausea, vomiting, polyuria, hypercalciuria, hypercalcemia and hyperphosphatemia.

“Vitamin D insufficiency and deficiency” is generally defined as having serum 25-hydroxyvitamin D levels below 30 ng/ml (see National Kidney Foundation, NKF, Am. J. Kidney Dis.

42:S1-S202 (2003), incorporated herein by reference).

As used herein the term “hypercalcemia” refers to a condition in a patient where the patient has corrected serum calcium levels above 10.2 mg/dL. Normal corrected serum levels of calcium for a human are between approximately 8.6 to 10.2 mg/dl.

As used herein the term “hyperphosphatemia” refers to a condition in a patient who has normal kidney function, or CKD stage 3-4, where the patient has serum phosphorus levels above 4.6. mg/dl. In a patient who has stage 5 CKD, hyperphosphatemia occurs when the patient has serum levels above 5.5 mg/dl. Normal values for serum phosphorus in a human are 2.5-4.5 mg/dl.

As used herein the term “plasma iPTH oversuppression” refers to a condition in a patient who has normal kidney function, or CKD stage 1-3, where the patient has plasma iPTH levels below of 15 pg/ml. In a patient who has stage 4 CKD, oversuppression of plasma iPTH occurs when the patient has plasma iPTH levels below 30 pg/ml. In a patient who has stage 5 CKD, oversuppression of plasma iPTH occurs when the patient has plasma ^ip T ^h levels below 100 pg/ml.

As used herein, the term “vitamin D hormone replacement therapy” refers to the administration to a patient of an effective amount of an active vitamin D hormone such as 1,25-dihydroxyvitamin D3 and/or 1,25-dihydroxyvitamin D2, optionally together with or other vitamin D metabolites and analogues that can substantially occupy the intracellular VDR.

As used herein, the term “substantially constant” with respect to the serum or blood level of vitamin D means that the release profile of the controlled release formulation (defined below) should not include increases in total levels in cholecalciferol and ergocalciferol serum or blood of more than about 10 nmol/l after administration of a unit dose, optionally for a period of at least 4 hours, 12 hours, 1 day, 2 days, 3 days, 4 days or 5 days. The term “substantially constant” with respect to the serum or blood level of 25-hydroxyvitamin D prohormones means that the release profile of any formulation administered as detailed hereinafter should not include transient increases in total serum levels. or blood 25-hydroxyvitamin D of more than about 3 ng/ml after administration of a unit dose. The term “substantially constant” with respect to the serum or blood level of an active vitamin D hormone preferably means that the release profile of the controlled release formulation should not include increases in total serum or blood levels of 1.25 -dihydroxyvitamin D of more than about 75 pg/ml each after administration of a unit dose, optionally over a period of preferably at least 30 minutes or 4 hours, etc.

As used herein, the terms "controlled release", "sustained release" and "modified release" are used interchangeably and refer to the release of the administered vitamin D compound in a manner that deviates from the release immediate. The terms “controlled release” and “modified release” optionally include delayed release characteristics. For example, a delayed release type of a controlled release formulation will be characterized by a Cmax at a time greater than the Cmax for an immediate release formulation. As another example, the release of an administered vitamin D compound (cholecalciferol and/or ergocalciferol) and/or 25-hydroxyvitamin D will preferably be at such a rate that total serum or blood levels of 25-hydroxyvitamin D are maintained or elevated by above predose levels for an extended period of time, for example 4 to 24 hours or even longer. As another example, a type of release sustained release of a controlled release formulation will be characterized by release at such a rate that total serum or blood levels of a 1,25-hydroxyvitamin D compound are maintained or elevated above pre-dose levels for an extended period of time, for example 20 to 40 minutes, 1 to 15 hours or even longer.

“Supraphysiological” in reference to intraluminal, intracellular, and blood levels of vitamin D refers to a total concentration of the vitamin D compound markedly greater than the generally stable levels observed in a vitamin D-replete subject, animal, or human patient during the course of any 24-hour period by laboratory measurement when vitamin D supplementation has been withheld for at least 30 days. “Adverse supraphysiological surge” refers to a local or serum concentration of a vitamin D compound that causes adverse effects such as excessive extrarenal production of hormones, which produces local adverse effects on calcium and phosphorus metabolism, inhibition of 25 -hepatic hydroxylation of vitamin D, increased catabolism of both vitamin D and 25-hydroxyvitamin D, hypercalciuria, hypercalcemia and/or hyperphosphatemia, with possible cardiovascular sequelae.

As used herein, the term “hyperparathyroidism” refers to primary hyperparathyroidism, secondary hyperparathyroidism, and hyperparathyroidism secondary to chronic kidney disease (stages 3, 4, or 5).

The term “subject” as used herein generally includes humans, mammals (e.g., dogs, cats, rodents, sheep, horses, cows, goats), veterinary animals, and zoo animals.

It is also specifically understood that any numerical value listed herein includes all values from the lowest value to the highest value, that is, all possible combinations of numerical values between the lowest value and the highest value should be considered listed are expressly indicated in this application. For example, if a concentration range or beneficial effect range is indicated as 1% to 50%, values such as 2% to 40%, 10% to 30%, or 1% to 3% are intended to be , etc., are expressly listed in this specification. These are only examples of what is specifically intended.

Administration of 25-hydroxyvitamin D3 in an immediate-release oral formulation has been tested as an alternative method to vitamin D supplementation. This approach, which was later abandoned, caused problems as do currently used vitamin D supplements. Specifically, it produced surges or spikes in blood and intracellular levels of 25-hydroxyvitamin D. Without wishing to be bound by any particular theory, it is believed that surges or spikes in blood and intracellular levels of 25-hydroxyvitamin D promote (a) competitive displacement of vitamin D hormones from serum vitamin D binding protein (DBP) and excessive administration of the displaced hormones to VDR-containing tissues, and (b) transiently excessive renal and extrarenal production of hormones of vitamin D, which together produce local abnormalities in calcium and phosphorus metabolism. Furthermore, these sudden increases in blood levels of 25-hydroxyvitamin D are thought to promote the catabolism of both vitamin D and 25-hydroxyvitamin D through 24- and/or 26-hydroxylation in the kidney and other tissues, decreasing the hepatic production of vitamin D prohormones, which unnecessarily hinders the efficient replacement of vitamin D insufficiency or deficiency and, additional local abnormalities in calcium and phosphorus homeostasis mediated by direct binding to VDR. Importantly, the immediate release of 25-hydroxyvitamin D3 is thought to promote its intestinal absorption through a mechanism that substantially involves transport to the liver in chylomicrons rather than bound to serum DBP. Delivery of 25-hydroxyvitamin D to the liver via chylomicrons is believed to significantly increase the likelihood of its catabolism.

One aspect of the disclosure relates to a solid or semi-solid waxy pharmaceutical formulation for controlled release of a vitamin D compound in the digestive tract of a subject ingesting the formulation. The formulation includes a controlled release waxy carrier, a lipoid agent, an oleaginous vehicle for the vitamin D compound, and a vitamin D compound. The formulation provides controlled release of the vitamin D compound incorporated therein. The formulation is free or essentially free of disintegrants.

The controlled release waxy carrier provides a formulation that is solid or semi-solid at room temperature and solid, semi-solid or liquid at body temperature, preferably semi-solid or liquid at body temperature. Examples of supports suitable for use include waxes, such as synthetic wax, microcrystalline wax, paraffin, carnauba wax and beeswax; polyethoxylated derivatives of castor oil, hydrogenated vegetable oils, glyceryl mono-, di- and tribehenates; long chain alcohols, such as stearyl alcohol, cetyl alcohol and polyethylene glycol, and mixtures of any of the above. Non-digestible waxy substances, such as solid paraffin, are preferred.

The waxy carrier is preferably present in an amount greater than about 5% of the formulation, based on the total weight of the formulation excluding any additional coating or coating (wt%). For example, the waxy support may comprise more than 5% by weight of the formulation, more than 10% by weight of the formulation, more than 15% by weight of the formulation, more than 20% by weight of the formulation, and more of 25% by weight of the formulation. The waxy support is preferably present in an amount of less than 50% by weight, less than 40% by weight, less than 35% by weight, or less than 30% by weight. Suitable ranges include 5% by weight to 35% by weight, from 15% by weight to 35% by weight and from 20 to 30% by weight. Examples include 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, 20% by weight, 21% by weight, 22% by weight , 23% by weight, 24% by weight, 25% by weight, 26% by weight, 27% by weight, 28% by weight, 29% by weight and 30% by weight.

The lipoid agent provides for the release of the vitamin D compound from the formulation into the digestive tract of the subject being treated. Without wishing to be bound by any particular theory of operation, it is believed that the lipoid agent may serve one or more preferred functions such as creating a microemulsion of the oleaginous carrier in the gastrointestinal fluid; providing prolonged gastric retention, for example through bioadhesive properties so that the formulation interacts with the mucosal layer of the stomach and/or intestine; and in increasing the absorption of the vitamin D compound. However, regardless of the mechanism of action, the invention is not limited by any particular mode of operation.

The components of the lipoid agent preferably are amphiphiles, in which the molecule or ion contains both hydrophilic and lipophilic moieties. These components can be defined by a numerical value based on the hydrophilic/lipophilic balance system (“HLB system”). The HLB scale is a numerical scale that ranges from 0 to approximately 20, with lower numbers indicating more lipophilic and hydrophobic substances, and higher numbers indicating more hydrophilic and lipphobic substances. The affinity of a compound for water, or for oily substances, is determined and its HLB value is assigned experimentally. The HLB of the hydrophobic support used herein will preferably be in a range from about 13 to about 18.

A variety of pharmaceutically acceptable lipoid agents can be incorporated into the formulation. The amount of the lipoid agent present in the formulation is preferably at least 5% by weight, at least 15% by weight, at least 35% by weight, at least 40% by weight or at least 45% by weight . Suitable ranges include from about 5% by weight to about 60% by weight, from about 20% by weight to about 60% by weight and from about 40% by weight to about 50% by weight.

In one embodiment, the lipoid agent is a lipophilic emulsifier having an HLB of less than 7 and comprises a member selected from the group consisting of mixed fatty acid monoglycerides; mixed fatty acid diglycerides; mixtures of mono- and diglycerides of fatty acids; lipophilic polyglycerol esters; glycerol esters including glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate and glyceryl dipalmitate; glyceryl lactoesters of fatty acids; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; sorbitan esters including sorbitan monostearate, sorbitan sesquiolate; fatty acids and their soaps including stearic acid, palmitic acid and oleic acid; and mixtures thereof, glyceryl monooleate, glyceryl dioleate, glyceryl monostearate, glyceryl distearate, glyceryl monopalmitate and glyceryl dipalmitate; glyceryl lactoesters of fatty acids; propylene glycol esters including propylene glycol monopalmitate, propylene glycol monostearate and propylene glycol monooleate; sorbitan esters including sorbitan monostearate, sorbitan sesquiolate; fatty acids and their soaps including stearic acid, palmitic acid and oleic acid; and mixtures thereof.

A preferred lipoid agent is selected from glycerides and derivatives thereof. Preferred glycerides are selected from the group consisting of medium or long chain glycerides, caprylocaproyl macrogolglycerides and mixtures thereof.

Preferred medium chain glycerides include, but are not limited to, medium chain monoglycerides, medium chain diglycerides, caprylic/capric triglyceride, glyceryl monolaurate, glyceryl monostearate, caprylic/capric glycerides, glyceryl monocaprylate, glyceryl, caprylic/capric linoleic triglyceride and caprylic/capric/succinic triglyceride.

Monoglycerides having a low melting point are preferred to make the formulation. Preferred monoglycerides include, but are not limited to, glyceryl monostearate, glyceryl monopalmitate, glyceryl monooleate, glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, etc., preferably glyceryl monostearate (GMS). GMS is a natural emulsifying agent. It is fat-soluble, but poorly soluble in water. GMS has an HLB value of 3.8. Another preferred monoglyceride is glyceryl monooleate (GMO). GMO is also a natural emulsifying agent; It is fat-soluble, but poorly soluble in water, and has an HLB value of 3.8.

In another embodiment, the glyceride is an absorption enhancer selected from caprylocaproyl macrogolglycerides. Caprylocaproyl macrogolglycerides that may be employed include, but are not limited to, polyethylene glycosylated glycerides, also known as polyglycolized glycerides or PEGylated glycerides. PEGylated glycerides that can be employed in the composition include, but are not limited to, mixtures of monoglycerides, diglycerides and triglycerides and monoesters and diesters of polyethylene glycol, polyethylene glycosylated almond glycerides, polyethylene glycosylated corn glycerides and polyethylene glycosylated caprylic / capric triglyceride. The absorption enhancer preferably has an HLB value of 13 to 18, more preferably 13 to 15.

A preferred absorption enhancer is known under the trade name GELUCIRE, and is commercially available from Gattefossé Corporation, Paramus, New Jersey, USA. GELUCIRE is a well-known excipient that is a family of fatty acid esters of glycerol and PEG esters. , also known as polyglycolized glycerides. GELUCIRE is used in various applications including the preparation of sustained release pharmaceutical compositions. GELUCIRE compounds are semi-solid, inert waxy materials that are amphiphilic and are available with variable physical characteristics such as melting point, HLB and solubilities in various solvents. They are surfactant in nature and disperse or solubilize in aqueous media forming micelles, microscopic globules or vesicles. They are identified by their melting point/HLB value. The melting point is expressed in degrees Celsius. One or a mixture of different grades of GELUCIRE excipient can be chosen to achieve the desired melting point characteristics and/or HLB value. The preferred GELUCIRE composition is GELUCIRE 44/14, a semi-solid waxy material with a melting point of 44°C and an HLB of 14.

Another preferred polyglycolized glyceride absorption enhancer is macrogol-8-caprylocaproyl glyceride (CAS No.

85536-07 and 84963-88-2). This is a mixture of mono-, di- and triesters of glycerol and PEG 400 with medium chain fatty acids (Ce-Cío) that is marketed, for example, by Gattefossé Corporation, Paramus, New Jersey, USA under the name LABRASOL commercial. lAb rAs OL has an HLB value of 14 and has the following composition by weight: C ₈ -C10 monoglycerides approximately 4%; C ₈ -C10 diglycerides approximately 17%; C ₈ -C10 triglycerides approximately 6%; C ₈ -C10 monoesters of PEG 400 approximately 14%; C ₈ -C10 diesters of PEG 400 approximately 36%; PEG 400 free approximately 20%; free glycerol approximately 3%.

Preferably the lipoid agent includes a mixture of a lipophilic emulsifier having an HLB of less than 7 and an absorption enhancer preferably having an HLB value of 13 to 18. The lipophilic emulsifier is preferably present in an amount in a range from about 20% by weight to about 50% by weight, preferably from about 30% by weight to about 40% by weight, and the absorption enhancer is preferably present in an amount of about 5 to about 20% by weight , preferably from about 8 to about 15% by weight.

The low melting points of many of the solid lipoid compositions provide a means of incorporating the pharmaceutically active ingredients therein at temperatures from about 0°C to about 50°C above their respective melting points, and then charging the melt ( solution and/or dispersion) in animal or vegetable gelatin capsules. The fusion solidifies inside the capsules after cooling them to room temperature.

The oil component serves as a carrier, preferably the primary carrier, for the vitamin D compound. Any pharmaceutically acceptable oil may be used. Examples include animal (e.g., fish), vegetable (e.g., soy), and mineral oils. The oil will preferably easily dissolve the vitamin D compound used. Preferred oleaginous components include nondigestible oils, such as mineral oils, particularly liquid paraffins and squalene. The oleaginous carrier preferably comprises from about 10% by weight to about 50% by weight of the formulation, more preferably from about 15% by weight to about 45% by weight, from about 20% to about 40% by weight, or from about 15% by weight to about 25% by weight. In a preferred embodiment, the liquid paraffin can be characterized by one or more of the following parameters: specific gravity of about 0.88 to 0.89; kinematic viscosity (40°C) from about 64 to about 70 cSt; molecular weight 424; % paraffinic hydrocarbons approximately 59; and pouring point -24°C. The ratio of the wax component to the oil component can be optimized to achieve the desired rate of release of the vitamin D compound. Therefore, if a heavier oil component is used, relatively less of the wax component can be used, and if uses a lighter oily component, then relatively more waxy component can be used.

Any vitamin D compound suitable for prophylactic and/or therapeutic use, and combinations thereof, is contemplated for inclusion in the formulation described herein. Vitamin D, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and other metabolites and analogs of vitamin D are also useful as active compounds in pharmaceutical compositions. Specific examples include, but are not limited to, vitamin D3 (cholecalciferol), vitamin D2 (ergocalciferol), 25-hydroxyvitamin D3, 25-hydroxyvitamin D2, 1a,25-dihydroxyvitamin D3, 1a,25-dihydroxyvitamin D2, 1a,25 -dihydroxyvitamin D4, and vitamin D analogues (including all hydroxy and dihydroxy forms), including, 1,25-dihydroxy-19-nor-vitamin D2 and 1a-hydroxyvitamin D3. In one type of embodiment, the vitamin D compound includes one or more hydroxy forms, such as a combination of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2. In some embodiments, the vitamin D compound is administered in a therapeutically effective amount (e.g., an amount effective to prevent or treat hypovitaminosis D and/or secondary hyperparathyroidism).

One aspect of the disclosure includes a composition comprising a controlled release formulation of cholecalciferol and/or ergocalciferol and a method of administering such formulation (in one embodiment, in high doses) to treat insufficiency and deficiency in 25-hydroxyvitamin D to a level of effectiveness hitherto unobtainable; without adverse supraphysiological surges in intraluminal, intracellular, and blood levels of cholecalciferol, ergocalciferol and 25-hydroxyvitamin D and their consequences; and no serious side effects associated with vitamin D supplementation, i.e. vitamin D toxicity.

Controlled release compositions are designed to contain concentrations of the cholecalciferol/ergocalciferol at or above the UL, and are prepared in such a way to effect a controlled, preferably substantially constant, release of the cholecalciferol/ergocalciferol over an extended period of time. Raising intraluminal, blood, or intracellular concentrations of any precursor increases prohormone production. Furthermore, the compositions may optionally be designed for delayed release into the ileum of the digestive tract of humans or animals. It is contemplated that in one type of embodiment the compositions will ensure a substantially constant concentration of cholecalciferol/ergocalciferol in the body and a more sustained blood level. By providing a slow and constant release of cholecalciferol/ergosterol over time, peaks in blood, intraluminal and intracellular vitamin D concentrations, i.e. adverse supraphysiological levels, are mitigated or eliminated.

Compositions containing vitamin D3 in a dose of more than 5,000 IU, or more than 7,500 IU, or more than 10,000 IU are contemplated. Compositions comprising a combination of cholecalciferol and ergocalciferol in a unit dose of at least 1,500 IU (combined), or at least 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 7,500, 8,000, 9,000, 10,000 are contemplated. , 11,000 , 12,000 or 12,500 IU. Also contemplated are such unit doses of less than 2000,000 IU, or less than 100,000 or 75,000 or 50,000 IU.

The invention also contemplates that doses may be given at intervals of once a day, once every other day, three times a week, twice a week, weekly or every 2 weeks. The cumulative dose taken each time can be 1,500 IU (cholecalciferol and ergocalciferol separately or combined), or at least 2,000, 2,500, 3,000, 4,000, 5,000, 6,000, 7,000, 7,500, 8,000, 9,000, 10,000, 11,00 0, 12,000 or 12,500 UI. Also contemplated are such unit doses of less than 2000,000 IU, or less than 100,000 or 75,000 or 50,000 IU. Such doses are preferred for use with adult humans.

Cholecalciferol and ergocalciferol can be included in any ratio, for example, from 9:1 to 1:9. It is contemplated that ratios including, but not limited to, 1:1, greater than 1:1 cholecalciferol:ergocalciferol, and less than 1:1 cholecalciferol:ergocalciferol, are useful in various embodiments.

For example, a combination of 1,500 IU of cholecalciferol and 1,500 IU of ergocalciferol in a single unit dose capsule and/or in a daily dose is contemplated. Combinations of 1,000 IU of cholecalciferol with 1,000 IU of ergocalciferol in a single unit dose capsule and/or in a daily dose and 2,000 IU of cholecalciferol with 2,000 IU of ergocalciferol in a single unit dose capsule and/or in a daily dose are also contemplated. daily dose. The initial dosage regimen of such a unit dose capsule may be based on baseline serum levels of 25(OH)D (ng/ml [nmol/l], for example as detailed in Table 1 below for a combination of 1,500 IU of cholecalciferol and 1,500 IU of ergocalciferol in a single unit dose capsule.

Table 1

To maintain serum 25(OH)D concentrations at 30 ng/ml or above, one such capsule daily may be administered to adult patients.

The invention also includes compositions comprising oral formulations of 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3 ("25-hydroxyvitamin D2/25-hydroxyvitamin D3") and methods of administering such formulations to treat 25-hydroxyvitamin insufficiency and deficiency. D without supraphysiological surges in intraluminal, intracellular and blood levels of 25-hydroxyvitamin D and their consequences; without producing substantially increased catabolism of the administered 25-hydroxyvitamin D; and without producing serious side effects associated with vitamin D supplementation, that is, vitamin D toxicity.

Controlled release compositions intended for administration according to the invention are preferably designed to contain concentrations of 25-hydroxyvitamin D2/25-hydroxyvitamin D3 of 1 to 1000 μg per unit dose and are prepared in such a way as to produce a controlled release or substantially constant of 25hydroxyvitamin D2/25-hydroxyvitamin D3, optionally in the ileum of the digestive system, of humans or animals for an extended period of time. Preferred doses include 1 to 1000 μg per unit dose, 1 to 600 jg, 1 to 400 jg, 1 to 200 jg, 1 to 100 jg, 5 to 90 jg, 30 to 80 jg, 20 to 60 jg, from 30 to 60 jg, from 35 to 50 jg, from 5 to 50 jg, and from 10 to 25 jg, for example, 20 jg, 25jg, 30 jg, 40 jg, 50 jg, 60 jg, 70 jg, 80 jg, 90 jg and 100 jg. The compositions may provide substantially increased absorption of 25-hydroxyvitamin D through transport in DBP and decreased absorption through transport in chylomicrons. The compositions may provide maintenance of substantially constant blood levels of 25-hydroxyvitamin D for 24 hours after the dosing period. By providing a gradual, sustained and direct release of 25-hydroxyvitamin D2/25-hydroxyvitamin D3 and absorption preferentially to circulating DBP (rather than chylomicrons), blood 25-hydroxyvitamin D concentration peaks can be mitigated or eliminated, intraluminal and intracellular, i.e., supraphysiological levels and related unwanted catabolism. Additionally, by providing a gradual and sustained release, serum levels of 25-hydroxyvitamin D can be increased and maintained more predictably than by administration of immediate-release oral formulations, allowing for consistent dosing and reducing or eliminating the need for monitoring. frequent of the patient.

In a preferred class of embodiments, the modified release formulation releases at least 70%, more preferably at least 80% of the vitamin D compound in the first 24 hours after dosing, for example, about 72%. .

Advantageously, 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 or combinations thereof can be administered together with other therapeutic agents, orally or intravenously according to the embodiments described above in dosage amounts from 1 to 100 μg per day, with preferred dosage amounts from 5 to 50 jg per day, for example, approximately 10 to 25 jg. Preferred doses will provide a mean increase in serum 25-hydroxyvitamin D3 of approximately 1 to 3 ng/ml.

In embodiments, the method of the invention is contemplated to include administration of a formulation described herein to raise and preferably also maintain blood 1,25-dihydroxyvitamin D levels at 25 pg/ml, 30 pg/ml. ml or greater, for example 25-65 pg/ml for an extended period, for example, at least one month, at least three months, at least six months, or longer.

In one aspect, a method of lowering or maintaining decreased serum parathyroid hormone in human patients includes administering to said patients an effective amount of an active vitamin D hormone, such as 1,25-dihydroxyvitamin D2 according to the disclosure herein to decrease o maintain decreased serum parathyroid hormone levels, preferably an amount that decreases PTH levels by at least 30%, or alternatively the amount necessary to reduce serum PTH levels to the target range for the CKD stage (for example for stage 3 it is 35-70 pg/ml (equivalent to 3.85-7.7 pmol/l), for stage 4 it is 70 110 pg/ml (equivalent to 7.7-12.1 pmol /l), and for stage 5 it is 150-300 pg/ml (equivalent to 16.5-33.0 pmol/l) (defined in K/DOQI guideline No. 1)).

In another aspect, the method includes administering to a patient suffering from hyperparathyroidism secondary to chronic kidney disease (stage 3, 4 or 5) an effective amount of an active vitamin D hormone such as 1,25-dihydroxyvitamin D2 according to the disclosure of the present document to decrease the serum PTH level.

The dose of a 1,25-dihydroxyvitamin D for oral administration is generally about 0.1 mg per week to 100 mg per week, preferably from about 0.7 mg per week to about 70 mg per week. , which can be separated into daily or other periodic doses, such as three times a week for concomitant administration with hemodialysis. In exemplary embodiments, an oral dose equivalent to approximately 1, 2, 3, 4, 5, 6, 7, 8 or 9 mg per day is contemplated.

In general, a 1,25-dihydroxyvitamin D compound is dispensed by a unit dosage form comprising from about 0.1 jg to about 10 jg per unit dose, for example from about 1 jg to about 4 jg, from about 2 jg up to about 10 jg, or from about 3 jg to about 5 jg.

Administration of a vitamin D hormone, such as 1,25-dihydroxyvitamin D2, as described herein, also allows for the efficient and predictable administration of a predetermined dose of a vitamin D hormone to a patient. The temporal and quantitative availability of active vitamin D hormone does not depend on activation in the liver or other metabolism. Accordingly, lower doses, compared to administration by other means, are considered possible to achieve equivalent effects, while optionally or preferably avoiding or reducing side effects, as described above.

The doses described herein are contemplated for any of the therapeutic methods described herein. It will be appreciated that the actual preferred amount of a vitamin D compound in a specific case will vary depending on the particular compositions formulated, the mode of application and the particular site being treated. Doses can be determined using conventional considerations, for example, by comparison usual of the differential activity of the hormone and a known agent, for example, by means of an appropriate conventional pharmacological protocol.

Specific doses for each particular patient may depend on a wide variety of factors, for example, age, body weight, general health, sex, diet, rate and mode of administration, rate of excretion, and the medications used in combination and the severity of the particular disorder to which the therapy is applied.

Patients in need of vitamin D supplementation include healthy subjects and subjects at risk of vitamin D insufficiency or deficiency, for example, subjects with CKD stage 1, 2, 3, 4, or 5; infants, children, and adults who do not drink vitamin D-fortified milk (e.g., lactose intolerant subjects, subjects with milk allergy, vegetarians who do not consume milk, and breastfed infants); subjects with rickets; subjects with dark skin (for example, in the US, 42% of African-American women between 15 and 49 years of age were deficient in vitamin D compared to 4% of white women); the elderly (who have a reduced ability to synthesize vitamin D and are also more likely to remain at home); adults in nursing homes (who are more likely to remain indoors, including individuals with Alzheimer's disease or mental illness); subjects who cover all exposed skin (such as members of certain religions or cultures); subjects who always use sunscreen (for example, applying sunscreen with a sun protection factor (SPF) value of 8 reduces vitamin D production by 95%, and higher SPF values may additionally reduce vitamin D ); subjects with fat malabsorption syndromes (including, but not limited to, cystic fibrosis, cholestatic liver disease, other liver diseases, gallbladder disease, pancreatic enzyme deficiency, Crohn's disease, inflammatory bowel disease, celiac disease, or surgical removal of part or all of the stomach and/or intestines); subjects with inflammatory bowel disease; subjects with Crohn's disease; subjects who have had small bowel resections; subjects with gum disease; subjects taking drugs that increase vitamin D catabolism, including phenytoin, fosphenytoin, phenobarbital, carbamazepine, and rifampin; subjects taking drugs that reduce vitamin D absorption, including cholestyramine, colestipol, orlistat, mineral oil, and fat substitutes; subjects taking drugs that inhibit vitamin D activation, including ketoconazole; subjects taking drugs that decrease calcium absorption, including corticosteroids; subjects with obesity (vitamin D deposited in body fat stores is less bioavailable); subjects with osteoporosis; and/or postmenopausal women. According to the Institute of Medicine's report on Dietary Reference Intakes for vitamin D, food consumption data suggest that median vitamin D intakes for both younger and older women are below current recommendations; Data suggests that more than 50% of younger and older women do not consume recommended amounts of vitamin D.

Optionally excluded from the methods of the invention described herein are the therapeutic treatment of subjects suffering from renal osteodystrophy (including osteomalacia and osteitis fibrosa cystica).

In other aspects, the compositions and methods of the invention are useful for the prophylactic or therapeutic treatment of vitamin D sensitive diseases, that is, diseases in which vitamin D, 25-hydroxyvitamin D or active vitamin D (e.g. 1,25-dihydroxyvitamin D) prevents the onset or progression of the disease, or reduces the signs or symptoms of the disease. Such vitamin D sensitive diseases include cancer (for example, breast, lung, skin, melanoma, colon, colorectal, rectal, prostate and bone cancer). 1,25-Dihydroxyvitamin D has been observed to induce cell differentiation and/or inhibit cell proliferation in vitro for a number of cells. Vitamin D sensitive diseases also include autoimmune diseases, for example, type I diabetes, multiple sclerosis, rheumatoid arthritis, polymyositis, dermatomyositis, scleroderma, fibrosis, Grave's disease, Hashimoto's disease, acute or chronic transplant rejection, acute or chronic graft versus host, inflammatory bowel disease, Crohn's disease, systemic lupus erythematosus, Sjogren's syndrome, eczema and psoriasis, dermatitis, including atopic dermatitis, contact dermatitis, allergic dermatitis and/or chronic dermatitis. Vitamin D sensitive diseases also include other inflammatory diseases, for example, asthma, chronic obstructive pulmonary disease, polycystic kidney disease, polycystic ovary syndrome, pancreatitis, nephritis, hepatitis and/or infection. Vitamin D-sensitive diseases have also been described to include hypertension and cardiovascular diseases. Therefore, the invention contemplates the prophylactic or therapeutic treatment of subjects at risk of or suffering from cardiovascular diseases, for example, subjects with atherosclerosis, arteriosclerosis, coronary artery disease, cerebrovascular disease, peripheral venous insufficiency, myocardial infarction, myocardial ischemia, ischemia brain, stroke, congestive heart failure, cardiomyopathy, obesity or other weight disorders, lipid disorders (for example, hyperlipidemia, dyslipidemia including diabetic associated dyslipidemia and mixed dyslipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hypercholesterolemia, and low HDL (high-density lipoprotein), metabolic disorders (e.g., metabolic syndrome, type II diabetes mellitus, type I diabetes mellitus, hyperinsulinemia, impaired glucose tolerance, insulin resistance, diabetic complication including neuropathy, nephropathy, retinopathy, diabetic foot ulcer and cataracts) and/ or thrombosis.

Diseases that may benefit from a modulation in the levels of vitamin D compounds include, but are not limited to: (i) in the parathyroid -- hypoparathyroidism, pseudohypoparathyroidism, secondary hyperparathyroidism; (ii) in the pancreas -- diabetes; (iii) in the thyroid -- medullary carcinoma; (iv) on the skin -- psoriasis; cicatrization; (v) in the lung -- sarcoidosis and tuberculosis; (vi) in the kidney -- chronic kidney disease, hypophosphatemic VDRR, vitamin D-dependent rickets; (vii) in bone -- anticonvulsant treatment, bone fibrogenesis imperfecta, osteitis fibrosa cystica, osteomalacia, osteoporosis, osteopenia, osteosclerosis, renal osteodystrophy, rickets; (viii) in the intestine -- glucocorticoid antagonism, idiopathic hypercalcemia, malabsorption syndrome, steatorrhea, tropical sprue; and (ix) autoimmune disorders.

In embodiments of the invention, the disease that benefits from a modulation in the levels of vitamin D compounds is selected from cancer, dermatological disorders (for example, psoriasis), parathyroid disorders (for example, hyperparathyroidism and secondary hyperparathyroidism), bone disorders (for example, osteoporosis) and autoimmune disorders.

The formulation can be prepared by procedures well known to those skilled in the art. Typically, pharmaceutically acceptable waxes, lipoid agents and oils are melted, if necessary, to provide a self-suspending liquid, thereby making it easier to obtain a homogeneous mixture. The vitamin D compound is added to the liquid carrier, for example dissolved in an alcohol such as anhydrous ethanol, and the ingredients are mixed to provide a homogeneous mixture. The mixture can be cooled and stored before further division into unit dosage forms, such as filled gelatin capsules.

In a preferred method, a portion of the oil carrier, solid wax and a lipophilic emulsifier are heated to a relatively high temperature (e.g., 65°C) and mixed before adding an absorption enhancer, followed by further mixing until it is homogeneous, then cooled to an intermediate elevated temperature (e.g., 50°C to 55°C). In a separate container, an antioxidant preservative and the rest of the oil carrier are mixed and heated to an intermediate elevated temperature (for example, 50°C), then combined and mixed with the wax mixture until a homogeneous solution is obtained. . Next, a solution of a vitamin D compound in alcohol is combined with the homogeneous waxy solution, mixed until a homogeneous solution is obtained, preferably filled into capsules, and then cooled to room temperature. In another preferred method, a portion of the oil carrier, solid wax and a lipophilic emulsifier are heated to a temperature of 55°C to 65°C and mixed before adding the absorption enhancer, followed by further mixing until homogeneous. . In a separate container, an antioxidant preservative and the rest of the oil carrier are mixed and heated to a temperature of 55°C to 60°C, then combined and mixed with the wax mixture until a homogeneous solution is obtained. Next, a solution of a vitamin D compound in alcohol is combined with the homogeneous waxy solution, mixed until a homogeneous solution is obtained, preferably filled into capsules, and then cooled to room temperature.

The formulation is preferably placed in capsules before administration to the patient in need of treatment. Such capsules may be hard or soft, and soft capsules are preferred. The formulation can be filled into gelatin capsules using standard capsule filling machinery, such as melting the formulation and injection filling into soft capsule shells.

The formulation and methods of use and making are contemplated to include embodiments that include any combination of one or more additional elements, features and optional steps, further described below, unless otherwise indicated.

Therefore, in one type of embodiment, the formulation further includes a preservative, such as an antioxidant. Butylated hydroxytoluene (BHT) is preferred.

In another type of embodiment, the vitamin D compound is administered in combination with one or more other therapeutic agents.

If the vitamin D compound is administered in combination with one or more other therapeutic agents, the proportions of each of the compounds in the combination to be administered will depend on the particular disease state to be addressed. For example, one may choose to administer orally 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3 with one or more calcium salts (intended as a calcium supplement or nutritional phosphate binder), bisphosphonates, calcimimetics, nicotinic acid, iron , phosphate binders, cholecalciferol, active vitamin D sterols, glycemic and hypertension control agents, various antineoplastic agents, and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade vitamin D agents. Additionally, one may choose to administer by intravenous 25-hydroxyvitamin D2 and/or 25-hydroxyvitamin D3 with cholecalciferol, ergocalciferol, active vitamin D sterols, glycemic and hypertension control agents, various antineoplastic agents and inhibitors of CYP24 and other cytochrome P450 enzymes that can degrade the agents of vitamin D. In practice, higher doses of the compounds of the present invention are used where therapeutic treatment of a disease state is the desired end, while lower doses are generally used for prophylactic purposes, it being understood that the specific dose administered in any given case will be adjusted according to the specific compounds being administered, the disease being treated, the condition of the subject, and the other relevant medical facts that may modify the activity of the drug or the response of the subject, as those skilled in the art are well aware. The matter.

As described above, the formulation is preferably filled into gelatin capsules, but may also be administered in pure form, or with one or more outer coating layers, such as an enteric coating. It is also contemplated that the formulation may be pressed into tablets, and in such cases one or more tabletting excipients may be included.

In the compositions and methods described herein, preferred steps, preferred components, preferred compositional ranges thereof, and preferred combinations of the above may be selected from several specific examples provided herein. For example, a preferred formulation includes 25-hydroxyvitamin D (e.g., 25-hydroxyvitamin D3, e.g., about 0.1% by weight (e.g., 0.12% by weight)), about 2% by weight. weight (for example, 2.32% by weight) of ethanol, approximately 10% by weight (for example, 9.75% by weight) of GELUCIRE 44/14, approximately 27% by weight (for example, 27.51% by weight) of solid paraffin, approximately 38% by weight (for example, 37.85% by weight) of GMS, approximately 22% by weight (for example, 22.43% by weight ) mineral oil, and optionally a small amount of preservative (e.g. 0.02% by weight BHT). A variation of this formulation will include approximately 20% solid paraffin and approximately 29% mineral oil.

Specifications for yet another preferred embodiment of a capsule, and a 50 μg embodiment, are shown in Table 2 below.

Table 2

Examples

The following examples illustrate specific formulations and methods for their preparation. The examples are provided for illustration and are not intended to limit the scope of the invention.

Example 1 - Modified Release Formulations

Nine oral vitamin D formulations were prepared according to Table 3 below by homogeneously mixing the identified components in the amounts shown and loading the mixtures into hard gelatin capsules. Formulation 9 is an immediate release formulation according to the prior art, where MIGLYOL 812N is the trade name for caprylic/capric triglycerides, available from CONDEA Chemie GmbH of Cranford, New Jersey, USA. The formulations were administered to groups from Yucatan miniature pigs (approximately 10 kg), in single doses equivalent to 250 jg of 25-hydroxyvitamin D3. Each group included five animals. An equivalent of 250 μg of 25-hydroxyvitamin D3 was administered to a tenth group of five Yucatan miniature pigs by intravenous injection.

Blood was collected predose and at 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 96, 168, 240, 336, 432, 504, 576, and 672 hours after dosing. Serum levels of 25-hydroxyvitamin D3 were assessed by liquid chromatography/mass spectrometry/mass spectrometry (LC MS/MS).

Graphs of the change in serum levels of 25-hydroxyvitamin D3 during the first 24 hours are shown for groups 1-8 in Figure 1 through Figure 8. Additionally, data for group 9, immediate release control are shown. represented with the data of group 7 in Figure 7. The concentration profiles show that the group 7 formulation according to the invention (a) produced a gradually increasing and sustained rise in serum levels of 25-hydroxyvitamin D3 during the first 24 hours , and (b) prevented a sudden increase in 25-hydroxyvitamin D3 levels.

Figure 9 to Figure 11 show graphs of the change in serum levels of 25-hydroxyvitamin D3 during the study period for groups 7, 9 and 10, respectively. Figure 12 shows an overlay plot of the data in Figure 9 and Figure 10 for groups 7 and 9, respectively.

The concentration profiles show that the group 7 formulation according to the invention produced a gradually increasing rise in serum levels of 25-hydroxyvitamin D3, prevented a sudden increase in 25-hydroxyvitamin D3 levels, and produced a sustained increase in 25-hydroxyvitamin D3 in serum for a long period of time.

In vitro dissolution testing of the same formulations (dissolution media; 0.056 lipase in Ctab/NaH ₂ PO ₄ buffer, pH 6.8) over a period of 120 minutes showed results generally consistent with in vivo data (e.g. formulations 2 and 7 showed a more gradual and incomplete rise in % dissolution, while the immediate release control showed 100% release at 30 minutes).

The data in Table 4 below show various pharmacokinetic parameters produced in the test subjects by administration of the group 7 formulation according to the invention in comparison with the group 9 prior art immediate release formulation and administration by injection IV of group 10. The data demonstrate that the group 7 formulation according to the invention avoided a concentration peak, provided a maximum concentration at a much later time than the immediate release dosage form and intravenous injection, and provided a clearance half-life longer than the comparable immediate release dosage form. The formulation of group 7 according to the invention produced a slower elimination of the administered 25-hydroxyvitamin D3 from the circulation compared to group 9.

A single dose of 250 μg of 25-hydroxyvitamin D3 administered according to the group 7 formulation of the invention to mini-pigs (approximately 10 kg) produced a rise of approximately 40 ng/ml in serum 25-hydroxyvitamin D3. A single dose of 50 μg of 25-hydroxyvitamin D3 to a human (approximately 60 kg) is expected to increase serum levels of 25-hydroxyvitamin D3 by approximately 1.4 ng/ml.

Table 4

Comparative data of Cmax, Tmax and bioavailability for the formulations of groups 1-6 and 8 are shown in table 5, below

Table 5

Example 2 - Pharmacokinetic studies in miniature pigs with oral capsules

The purpose of the study was to evaluate the systemic absorption of 25-hydroxyvitamin D3 in male Yucatan pigs (~45 kg body weight) after administration of: a) 1 x 250 μg modified release (LM) capsule of 25-hydroxyvitamin D3, b) 2 x 250 jg LM capsules, c) 4 x 250 jg LM capsules, d) 1 x 1000 jg LM capsule, e) 1 x 250 jg 25-hydroxyvitamin D3 immediate release (LI) capsule , and f) 1 x 250 jg LM capsule administered on 3 consecutive days.

The LM formulations were prepared based on the formulation of example 1, group 7, above. In the case of the 1000 jg LM capsule, the higher concentration of 25-hydroxyvitamin D3 was compensated by a relative decrease in ethanol.

To prepare the IL formulation, 25-hydroxyvitamin D3 (0.12% w/w; 250 μg per capsule) was dissolved in USP ethanol (2.32% w/w, solubilizer) and mixed with USP corn oil (97 .54% w/w; main vehicle) and butylated hydroxytoluene (0.02% w/w; antioxidant). Corn oil solution (250 mg) was loaded into size 0 two-piece hard gelatin capsules.

Eight male Yucatan miniature pigs per group were each administered a dose based on the dosing schedule in Table 6 below. Blood was collected from the animals before the first dose and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours after the first dose. Animals in group 6 were administered a second and third dose immediately after collection of the 24- and 48-hour blood samples, respectively. 25-hydroxyvitamin D3 was assayed in all collected samples. Ionized calcium and total calcium were determined in the samples collected from the animals in group 1 and group 5 at the following times: predose and at 0.5, 1.2, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours after the first dose.

Table 6

25-Hydroxyvitamin D3 was assayed in pig serum using solid phase extraction (SPE) with detection by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Serum samples were baseline corrected to exclude endogenous 25-hydroxyvitamin D3 concentrations from pharmacokinetic analysis. To achieve this, the predose concentration of 25-hydroxyvitamin D3 of each animal was subtracted from each of the post-dose concentrations. Serum samples below 1 ng/ml (lower limit of quantification) were assigned a value of zero.

The pharmacokinetic parameters are described in table 7.

Table 7

Dose-normalized pharmacokinetic parameters for groups 1 to 3 are described in Table 8.

Table 8

For the groups administered 1, 2, and 4 capsules (250 μg LM capsules), there was an increase in exposure as a function of dose. Dose proportional exposure occurred at doses of 1 x 250 jg and 2 x 250 jg, while slightly less than proportional exposure was observed between doses of 2 x 250 jg and 4 x 250 jg. The average time at which the maximum concentration (Tmax) was reached was between 25.5 and 30.5 hours.

Comparison of exposure from a single capsule (1 x 1000 jg) versus four capsules (4 x 250 jg) indicated greater exposure in animals dosed with multiple capsules. Dose-independent parameters, such as mean Tmax, were similar for both dosing strategies.

Comparison of the modified release formulation of 25-hydroxyvitamin D3 (LM) (group 1) with the LI formulation (group 5), indicated that the LM formulation prevented a peak in serum 25-hydroxyvitamin D3 concentration. The relative bioavailability of the LM formulation when compared to the LI formulation was approximately 77%. Animals receiving the LM formulation showed a mean Tmax of 26.5 hours indicating a significant delay compared to animals receiving the LI formulation (Tmax = 5.75 hours).

Exposure was assessed in animals receiving 1 x 250 μg LM capsule on days 1, 2, and 3. The mean increase in 25-hydroxyvitamin D3 concentration over baseline 24 hours after dosing was 17.3. 31.5 and 43.9 ng/ml after the first, second and third doses, respectively.

Figure 13 to Figure 18 show the mean pharmacokinetic profile for animals in groups 1-6, respectively. Figure 19 shows a comparison of the pharmacokinetic profiles for the LM and LI formulations of 250 jg of 25-hydroxyvitamin D3.

Example 3 - Systemic exposure studies in miniature pigs with oral capsules

The purpose of this study was to evaluate the increase in systemic 25-hydroxyvitamin D3 concentrations in healthy normal male Yucatan pigs (~50-60 kg body weight) maintained on a diet that included adequate vitamin D intake, after daily administration of the following: a) 25 jg capsules of 25-hydroxyvitamin D3 immediate release (LI) (group 1), b) 25 jg capsules of 25-hydroxyvitamin D3 modified release (LM) (group 2) , and c) capsules of 125 jg of LM of 25-hydroxyvitamin D3 (group 3), for 21 days.

The LM formulations were prepared based on the formulation of example 1, group 7, above. Differences in 25-hydroxyvitamin D3 concentration were compensated for by relative changes in ethanol.

To prepare the IL formulation, 25-hydroxyvitamin D3 (0.12% w/w; 250 μg per capsule) was dissolved in USP ethanol (2.32% w/w, solubilizer) and mixed with USP corn oil (97 .54% w/w; main vehicle) and butylated hydroxytoluene (0.02% w/w; antioxidant). The corn oil solution (205 mg) was filled into two-piece hard gelatin capsules of size 0.

Each of eight Yucatan miniature pigs per group were administered a daily dose based on the dosing schedule in Table 9, below.

Table 9

Blood was collected from the animals before the first dose and daily at 24 hours after the daily dose, before the subsequent dose. 25-Hydroxyvitamin D3 was assayed in pig serum using solid phase extraction (SPE) with detection by high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). Total serum calcium was determined in samples collected from the animals at the following times: predose (day 0) and 24 after the last dose (day 21).

In all three groups, the mean predose serum concentrations of 25-hydroxyvitamin D3 were approximately 26 ng/ml. After 21 doses, an increase in serum 25-hydroxyvitamin D3 was observed in all animals. After repeated administration of 25 μg capsules of LM or LI, serum 25-hydroxyvitamin D3 concentration increased to levels above 30 ng/ml and began to stabilize at approximately 45 and 55 ng/ml, respectively at approximately on day 17 to 18. After the administration of a single dose, the increase in serum 25-hydroxyvitamin D3 between the two regimens was comparable (3.84 versus 4.18 ng/ml). On the other hand, at the end of dosing the increase was approximately 60% greater for the animals administered the LI formulation. This finding indicates that the bioavailability of LM capsule is comparable to that of LI after a single dose, but that LM capsules present a method for repeated dosing of 25-hydroxyvitamin D3 in which 25-hydroxyvitamin D3 Systemic D3 can be increased gradually.

Animals administered the 125 jg LM capsules showed higher levels of 25-hydroxyvitamin D3 in serum. Administration of a 5-fold higher dose (125 jg vs 25 jg LM capsules) produced approximately a 5-fold increase in 25-hydroxyvitamin D3 after single and repeated doses.

This finding indicates that exposure from LM capsules is dose proportional from 25 to 125 μg.

The effect of LI and LM capsule administration on serum calcium concentration was investigated. After administration of 21 doses of LI or LM, serum calcium levels did not change from predose baseline levels. This finding indicates that LM 25-hydroxyvitamin D3 capsules can be used to increase serum 25-hydroxyvitamin D3 levels above 100 ng/ml without producing an increase in serum calcium.

The profiles of mean uncorrected serum 25-hydroxyvitamin D3 concentration versus time for groups 1 to 3 are illustrated in Figure 20. The profiles of mean baseline corrected serum 25-hydroxyvitamin D3 concentration versus time for the groups 1 to 3 are illustrated in Figure 21, Figure 22 and Figure 23, respectively.

Figure 24 shows the mean change in parathyroid hormone levels for group 1 animals from predose to day 21, and figure 25 shows the mean change in parathyroid hormone levels for group 2 animals from predose to day 21. day 21. Both immediate-release and LM formulations increase serum 25-hydroxyvitamin D3; however, the immediate-release formulation produced undesirable pharmacological decreases in PTH. The LM formulation does not produce acute supraphysiological reductions in PTH and allows a gradual decrease in PTH, which is believed to be associated with the physiological adaptation to markedly increasing 25-hydroxyvitamin D3 levels. The LM formulation should allow for higher serum 25-hydroxyvitamin D3 levels to be obtained without safety concerns associated with pharmacological lowering of PTH.

Example 4 - Pharmacokinetic studies in Beagle dogs with oral capsules

Modified-release 25-hydroxyvitamin D3 capsules were administered daily to Beagle dogs (10 kg) for 13 consecutive weeks. The LM formulations were prepared based on the formulation of example 1, group 7, above. Differences in 25-hydroxyvitamin D3 concentration were compensated for by relative changes in ethanol.

The capsules were administered orally, as shown in table 10 below.

Table 10

Dogs were bled before the first dose and at specific times after the first dose, up to 13 weeks (92 days). Serum was generated and 25-hydroxyvitamin D3 in the serum was assayed using a liquid chromatography-tandem mass spectrometry method.

Profiles for mean serum 25-hydroxyvitamin D3 concentration versus time for groups 1 to 5 are illustrated in Figure 26.

Example 5 - Release after dissolution

Figure 27 shows a solution release profile for 250 μg capsules according to Example 2 above, which showed an average release of approximately 72% of 25-hydroxyvitamin D3 in 24 hours. As described above, preferably the formulation releases approximately 80% of the drug in the first 24 hours.

Example 6 - Efficacy study in healthy adult male volunteers with vitamin D insufficiency

We examined the effectiveness of three different vitamin D formulations in restoring serum 25-hydroxyvitamin D to optimal levels (>30 ng/ml) in a 23-day study of healthy nonobese men diagnosed with vitamin D insufficiency. The formulations (formulation #1) is a soft gelatin capsule containing 30 μg of 25-hydroxyvitamin D3 prepared as described in Example 1, Group 7, above. The second formulation (formulation #2) is an identical-appearing immediate-release soft gelatin capsule containing 50,000 IU of ergocalciferol dissolved in medium-chain triglyceride oil. The third formulation (formulation #3) is an immediate-release soft gelatin capsule, also identical in appearance, containing 50,000 IU of cholecalciferol dissolved in medium-chain triglyceride oil. A total of 100 men participate in this study Healthy whites and African Americans, all aged 30 to 45 years and having serum 25-hydrovitamin D levels between 15 and 29 ng/ml (inclusive). All subjects refrain from taking other vitamin D supplements for 60 days prior to the start of the study and continuing until completion of the study, and from significant sun exposure. On day 1 and 2 of the study, all subjects provide fasting morning blood samples to establish pretreatment baseline serum 25-hydroxyvitamin D values. On the morning of day 3, subjects provide an additional fasting blood sample (t=0), are randomly assigned to one of four treatment groups, and are dosed with a single test capsule before eating breakfast. : Subjects in group #1 each receive a single capsule of formulation #1, and subjects in groups #2 and #3 each receive a single capsule of formulation #2 or formulation #3, respectively. Subjects in group #4 receive a matching placebo capsule. Subjects in group #1 each receive one additional capsule of formulation #1 on the mornings of days 4 to 22 before breakfast, but subjects in groups #2, #3 and #4 do not receive additional capsules. A fasting morning blood sample is drawn from each subject, regardless of treatment group, on days 4, 5, 6, 10, 17, and 23 (or 1,2, 3, 7, 14, and 20 days after start dosing). Contained levels of 25-hydroxyvitamin D in all collected blood are analyzed, and the data are analyzed by treatment group after correcting for baseline values. Subjects in all four treatment groups show baseline serum 25-hydroxyvitamin D levels of approximately 16 to 18 ng/ml based on analyzes of fasting blood samples drawn on days 1 to 3. Subjects in group # 4 (control group) show no significant changes in mean serum 25-hydroxyvitamin D throughout the course of the study. Subjects in group #1 show regularly increasing serum mean 25-hydroxyvitamin D reaching at least 30 ng/ml by day 23. In marked contrast, subjects in group #2 show marked increases in mean 25-hydroxyvitamin D in serum during the first few days after dosing, which peaks at 29 ng/ml and then decreases rapidly thereafter. At the end of the study, serum 25-hydroxyvitamin D is significantly lower than baseline in group #2. Subjects in group #3 show continuous increases in mean serum 25-hydroxyvitamin D during the first 2 weeks after dosing with a gradual, but progressive decrease occurring thereafter. At the end of the study, mean serum 25-hydroxyvitamin D is below 30 ng/ml, being only approximately 11 ng/ml higher than pretreatment baseline. Data from this study demonstrate that administration of 600 μg of 25-hydroxyvitamin D3, formulated as described herein and administered at a dose of 30 μg per day for 20 days, is substantially more effective in restoring low levels. serum 25-hydroxyvitamin D at optimal levels than immediate-release formulations of 50,000 IU of ergocalciferol or cholecalciferol administered in single doses, as currently recommended by the NKF and other leading experts in oral vitamin D replacement therapy.

Example 7 - Efficacy study in patients with CKD stage 4 and secondary hyperparathyroidism associated with vitamin D insufficiency

Examining the efficacy of immediate-release and modified-release 25-hydroxyvitamin D3 in restoring total serum 25-hydroxyvitamin D to optimal levels (>30 ng/mL) in a 6-month study of adult male and female patients with CKD in stage 4 and secondary hyperparathyroidism associated with vitamin D insufficiency. Two formulations are used in the study. One of the formulations (formulation #1) is a soft gelatin capsule containing 40 μg of 25-hydroxyvitamin D3 in a modified release formulation. The second formulation (formulation #2) is a soft gelatin capsule containing 40 μg of 25-hydroxyvitamin D3 in an immediate release formulation. A total of 100 subjects participate in this study, all of them aged between 30 and 70 years and have serum 25-hydroxyvitamin D levels between 15 and 29 ng/ml (inclusive) and intact parathyroid hormone (iPTH) levels in serum above the target levels published in the current K/DOQI guidelines at the time of enrollment. All subjects refrain from taking other vitamin D supplements for 60 days prior to the start of the study and continuing until completion of the study, and from significant sun exposure. All subjects begin daily dosing with two capsules of formulation #1 or formulation #2. Total serum 25-hydroxyvitamin D is measured at biweekly intervals and serum iPTH is determined at quarterly intervals. After 1 month, the daily dose of both formulations remains unchanged in patients whose total serum 25-hydroxyvitamin D is between 50 and 90 ng/ml, is increased by one capsule in patients whose total serum 25-hydroxyvitamin D is between 50 and 90 ng/ml. below 50 ng/ml and is decreased by one capsule per day in patients whose total serum 25-hydroxyvitamin D is above 90 ng/ml. Additional adjustments are made to the daily dose to maintain total serum 25-hydroxyvitamin D between 50 and 90 ng/mL. Dosing with both formulation #1 and #2 continues indefinitely, as long as hypercalcemia, hypercalciuria, and hyperphosphatemia do not develop, in which case appropriate dosage adjustments are made. After 6 months, total serum 25-hydroxyvitamin D levels of the subjects are found to remain stable between 50 and 90 ng/ml with treatment with formulation #1 and serum ^ip T ^h is found to remain stable. at levels consistent with the objectives published in the K/DOQI guidelines. The incidence of hypercalcemia, hypercalciuria and hyperphosphatemia are rare once stable dosing has been achieved. In contrast after 6 months, total serum 25-hydroxyvitamin D levels of the subjects are not found to remain stable between 50 and 90 ng/ml with treatment with formulation #2 and serum iPTH does not reach consistent levels. with the objectives published in the K/DOQI guidelines. The incidence of hypercalcemia, hypercalciuria, and hyperphosphatemia are substantial.

The data from this study demonstrate that the modified release formulation of 25-hydroxyvitamin D3 is effective in increasing serum 25-hydroxyvitamin D without producing unacceptable side effects related to calcium and PTH metabolism.

Claims (17)

1. A composition comprising an oral formulation of 25-hydroxyvitamin D3 for use in a method of treating secondary hyperparathyroidism in a human patient suffering from chronic kidney disease, wherein the method of treatment comprises administering the composition to the patient, in where the patient is treated without causing supraphysiological increases in blood 25-hydroxyvitamin D3, and wherein the pharmaceutical composition comprises 25-hydroxyvitamin D3 together with a release modifying agent that controls the release rate of the vitamin D compound from the dosage form to reduce Cmax and/or delay Tmax and/or decrease Cmax24h/C24h 2. The pharmaceutical composition for use in a treatment method according to claim 1 wherein the patient suffers from stage 3 stage 4 chronic kidney disease. 3. The pharmaceutical composition for use in a treatment method according to claims 1 or 2 wherein the patient suffers from chronic kidney disease associated with a glomerular filtration rate (GFR) below about 60 ml/min/1, 73 m2. 4. The pharmaceutical composition for use in a treatment method according to any of the preceding claims wherein the patient to be treated has low total serum levels of 25-hydroxyvitamin D at the beginning of treatment. 5. The pharmaceutical composition for use in a treatment method according to claim 4, wherein the patient to be treated has total serum levels of 25-hydroxyvitamin D below 30 ng/mL at the beginning of treatment. 6. The pharmaceutical composition for use in a treatment method according to claims 4 or 5, wherein the treatment method comprises administering the composition to the patient in such a way that the insufficiency of 25-hydroxyvitamin D and / or the deficiency in the patient is treated without causing supraphysiological increases in blood 25-hydroxyvitamin D3. 7. The pharmaceutical composition for use in a treatment method according to any of the preceding claims wherein the patient is an adult human. 8. The pharmaceutical composition for use in a treatment method according to any of the preceding claims wherein the release modifying agent is an enteric coating. 9. The pharmaceutical composition for use in a treatment method according to any of the preceding claims wherein the treatment method: (a) The maximum serum concentration of 25-hydroxyvitamin D3 over a dose range (Cmax) is reduced compared to the Cmax for an equivalent amount of 25-hydroxyvitamin D3 administered by bolus IV injection and/or an oral dosage form immediate release, or (b) the ratio of the maximum serum concentration in the 24 hours after administration of 25-hydroxyvitamin D3 to the concentration 24 hours after administration (Cmax24h/C24h) is reduced compared to a equivalent amount of 25-hydroxyvitamin D3 administered by bolus IV injection and/or by an immediate-release oral dosage form, or (c) the time for the plasma concentration of 25-hydroxyvitamin D3 to reach its maximum in a dose range after administration (Tmax) increases compared to the Tmax for an equivalent amount of 25-hydroxyvitamin D3 administered by injection IV bolus and/or by an oral immediate-release pharmaceutical form. 10. The pharmaceutical composition for use in a treatment method according to claim 9, wherein Cmax is reduced by a factor of at least 20%. 11. The pharmaceutical composition for use in a treatment method according to claim 9, wherein Tmax is increased by a factor of at least 25%. 12. The pharmaceutical composition for use in a treatment method according to claim 9, wherein Cmax24h/C24h is reduced by a factor of at least 20%. 13. The pharmaceutical composition for use in a treatment method according to any of the preceding claims, wherein the 25-hydroxyvitamin Dase is administered orally in an amount ranging from 1 to 100 μg, preferably 5 to 100 μg per day. 14. The pharmaceutical composition for use in a treatment method according to any of the preceding claims, wherein the 25-hydroxyvitamin Dase is administered orally in an amount ranging from 200 to 400 μg. 15. The pharmaceutical composition for use in a treatment method according to any of the preceding claims, wherein the 25-hydroxyvitamin is administered orally in an amount ranging from 5 to 80 μg, preferably from 30 to 80 μg, more preferably from 30 to 60 μg. 16. The pharmaceutical composition for use in a treatment method according to claim 15, wherein the 25-hydroxyvitamin Dase is administered orally in an amount of 10 μg. 17. The pharmaceutical composition for use in a treatment method according to claim 15, wherein the 25-hydroxyvitamin Dase is administered orally in an amount of 30 or 60 μg. The pharmaceutical composition for use in a treatment method according to any of claims 13 to 17, wherein 25-hydroxyvitamin Da is administered orally once a day.